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Progesterone Receptor, and HER2 in Breast Cancer

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Progesterone Receptor, and HER2 in Breast Cancer Modern Pathology (2010) 23, S52–S59 S52 & 2010 USCAP, Inc. All rights reserved 0893-3952/10 $32.00 Issues and updates: evaluating estrogen receptor-a, progesterone receptor, and HER2 in breast cancer D Craig Allred Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA There are currently three prognostic/predictive biomarkers used in routine clinical management of patients with breast cancer, and their assessment is mandatory. They include estrogen receptor-alpha (ERa), progesterone receptor (PgR), and the HER2 oncogene/oncoprotein. This paper briefly reviews the assessment of ERa, PgR, and HER2 in breast cancer, emphasizing recent progress and persistent controversies. Modern Pathology (2010) 23, S52–S59; doi:10.1038/modpathol.2010.55 Keywords: breast cancer; immunohistochemistry; estrogen receptor; progesterone receptor; HER2 Immunohistochemistry (IHC) has an important role and new methodologies). HER2 is further along than in the assessment of prognostic and predictive hormone receptors on many of these issues, and will factors in invasive breast cancer (IBC) today. Prog- be discussed first. nostic factors are defined as clinical, pathological, and biological features associated with the innate aggressiveness of untreated IBCs and, if adverse HER2 oncogene/oncoprotein enough, usually result in the use of additional (ie, adjuvant) therapies following surgery. Predictive HER2 (also referred to as HER2/neu and erbB2)is factors, in contrast, are defined as features that a proto-oncogene located on chromosome 17.9 It predict the likelihood of responding to specific encodes a tyrosine-kinase receptor residing on the types of adjuvant therapies. Many features have surface membrane of breast epithelial cells.10 HER2 both prognostic and predictive significance to forms complexes with similar proteins (such as varying degrees. Although a large number of erbB1, erbB3, and erbB4), which act as receptors for potentially useful factors have been identified,1–4 several ligands (such as epidermal growth factor, only three are currently used in routine clinical heregulin, and amphiregulin), which regulate many practice and their assessment is mandatory. These normal cellular functions, including proliferation, include the estrogen receptor-alpha (ERa), the survival, and apoptosis.11–13 Many studies during progesterone receptor (PgR), and the HER2 onco- the past 25 years have shown that the HER2 gene is gene/oncoprotein. IHC is the most commonly used amplified in up to 30% IBCs, and that amplification method of assessing these factors, although fluor- is highly correlated with overexpression of the escent in situ hybridization (FISH) also has a protein.11,12 The rate is closer to 15% today, which prominent role in HER2 testing.5–8 This presentation is probably because of screening mammography briefly reviews the assessment of these biomarkers detecting early-stage tumors before amplification in breast cancer, with special emphasis on standar- has occurred. dization, validation, and other issues of importance The relationship between HER2 status and clin- during the past 5 years (such as new clinical ical outcome is complex, and varies with the setting. applications, testing error rates, testing guidelines, There is a weak but significant association between poor outcome and ‘positive’ (ie, amplified and/or overexpressed) HER2 in patients receiving no addi- Correspondence: Professor DC Allred, MD, Department of tional therapy after initial surgery, which represent a Pathology and Immunology, Washington University School of small minority of patients today.14,15 Most patients Medicine, 660 S. Euclid Avenue, Campus Box 8118, St Louis, MO 63110, USA. receive some type of adjuvant therapy, and the E-mail: [email protected] association between HER2 status and outcome Received 25 January 2010; accepted 26 January 2010 seems to depend on the type of therapy.14–22 For www.modernpathology.org Evaluating ERa, PgR, and HER2 in breast cancer DC Allred S53 example, many studies suggest that HER2-positive implemented only 2 years ago, studies are beginning IBCs are resistant to certain types of cytotoxic to show that they have resulted in substantial chemotherapies (eg, the combination of cytoxan- improvement of testing accuracy.34 Figure 1 high- methotrexate-5-fluoracil) but sensitive to others (eg, lights the history, assays, clinical utility, problems, anthracyclines and taxanes). Other studies suggest and solutions represented by the ASCO/CAP testing that positive HER2 status may be associated with guidelines for HER2 testing. resistance to hormonal therapies, although not all agree and this issue remains somewhat controver- sial.21,23 The most promising and useful findings Estrogen receptor-a come from recent studies showing that HER2- positive tumors respond favorably to new anti- ERa is as a nuclear transcription factor activated by body-based therapies, which specifically target the estrogen to regulate growth and differentiation of HER-2 protein, such as trastuzumab,22,24 and the normal breast epithelial cells.35–37 These pathways main reason for assessing HER-2 status today is to remain operative to varying degrees in IBCs, includ- identify candidates for targeted therapy. Although ing estrogen-stimulated growth of tumor cells trastuzumab was originally demonstrated as being expressing ERa, which is detrimental.36–38 ERa effective in HER2-positive metastatic disease, more expression has been measured in IBCs for almost recent clinical trials have demonstrated significant 40 years. During the first 20–25 years, it was benefit as adjuvant therapy for women with less measured by radiolabeled biochemical ligand (ie, advanced HER2-positive breast cancer.25–28 For ex- estrogen)-binding assays (LBAs) on whole tissue ample, the NSABP-B31 clinical trial, which rando- extracts prepared from fresh-frozen tumor samples, mized patients with HER2-positive breast cancer to which was costly and difficult. Many studies using adjuvant chemotherapy±trastuzumab, showed a LBAs in large randomized clinical trials showed that 52% improvement in disease-free survival with ERa was a relatively weak prognostic factor but a trastuzumab, which is remarkable. very strong predictive factor for response to hormo- There has been a long and persistent controversy nal therapies, such as tamoxifen.38 Tamoxifen, about whether it is best to evaluate HER2 status by which binds ERa and blocks estrogen-stimulated measuring protein expression by IHC or gene growth, has been shown to significantly reduce amplification by FISH. Although there are vocal disease recurrence and prolong life in patients with proponents of both methods, many studies have ERa-positive IBCs.38,39 The clinical response to shown that, when properly performed, there is a newer types of hormonal therapies, such as the very strong correlation between IHC and aromatase inhibitors, which suppress the produc- FISH,8,15,29,30 and that they are equivalent (and tion of estrogen, is also dependent on the status of sometimes complimentary) in clinical utility. ERa, and only positive tumors benefit.40–42 The Approximately 70% of breast cancers show little primary reason for assessing ERa is its ability to or no protein expression, a normal gene copy predict response to these hormonal therapies. number, and do not respond to trastuzumab. Although the clinical utility of assessing ERa was Another roughly 15% show low-to-intermediate initially based almost entirely on studies using levels of protein expression, the gene is amplified technically standardized LBAs, beginning in the (usually at low levels) in about a third of these cases, early 1990s, laboratories around the world aban- and there is still uncertainty regarding how well this doned LBAs in favor of IHC, which is used for group responds. The remaining 15% of cases show nearly all testing today. very strong membrane staining, indicating high There are advantages to using IHC over LBAs, levels of protein expression, the gene is almost especially its ability to measure ERa on routine always amplified in these tumors, and they show the formalin-fixed paraffin-embedded samples, elimi- best response in any setting to trastuzumab, as well nating the need for fresh-frozen samples and the as newer and more effective therapies targeting onerous infrastructure required to provide it. Other HER2.16,31 advantages include lower cost, better safety, as well A particularly notable recent issue regarding as superior sensitivity and specificity in the sense HER2 testing is the joint publication of guidelines that the assessment of ERa is restricted to tumor for HER2 testing by the American Society of Clinical cells under direct microscopic visualization, inde- Oncologists (ASCO) and College of American pendent of tumor cellularity or the presence of Pathologists (CAP).8 They were developed to im- benign epithelium, which is problematic for LBAs. prove substantial inaccuracies in HER2, which were For all these reasons and more, IHC was approved revealed primarily in association with large clinical by the CAP and ASCO for routine clinical use.5,6 trials in which results from laboratories of enrolling However, despite these approvals, there are signifi- institutions were compared with testing by expert cant problems with IHC that persist today, including central laboratories. They consisted of false-negative the widespread use of diverse staining procedures of and false-positive IHC results up to 20%,32,33 and unequal quality and
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